Department of Molecular, Cellular and Craniofacial Biology, University of Louisville, 501 S. Preston St., Louisville, KY 40202, USA.
Toxicology. 2011 Nov 28;290(1):31-41. doi: 10.1016/j.tox.2011.08.013. Epub 2011 Aug 27.
Mitochondrial dysfunction has been implicated in chemical toxicities. The present study used an in vitro model to investigate the differential expression of metabolic pathways during cellular stress in p53-efficient embryonic fibroblasts compared to p53-deficient cells. These cell lines differed with respect to NADH/NAD(+) balance. This ratio constitutes a driving force for NAD- and NADH-dependent reactions and is inversed upon exposure to Rotenone (complex I inhibitor). Rotenone perturbed the structure of the elongated fibrillar tubulin network and decreased mRNA expression of tubulin genes both suggesting reprogramming and reorganization of the cytoskeleton in both cell lines. These changes were reflected in the abundance of specific mRNA and microRNA (miRNA) species as determined from genome-based analysis. Changes in mRNA and miRNA expression profiles reflected differences in energy utilizing pathways, consistent with the notion that the p53 pathway influences the cellular response to mitochondrial dysfunction and that at least some control may be embedded within specific mRNA/miRNA networks in embryonic cells.
线粒体功能障碍与化学毒性有关。本研究使用体外模型，研究了 p53 有效胚胎成纤维细胞与 p53 缺陷细胞在细胞应激过程中代谢途径的差异表达。这些细胞系在 NADH/NAD(+)平衡方面存在差异。该比例构成了 NAD-和 NADH 依赖性反应的驱动力，而在接触鱼藤酮（复合物 I 抑制剂）时会发生反转。鱼藤酮扰乱了拉长的纤维状微管网络的结构，并降低了微管基因的 mRNA 表达，这表明细胞骨架在两种细胞系中都发生了重编程和重组。这些变化反映在特定 mRNA 和 microRNA（miRNA）种类的丰度上，这是从基于基因组的分析中确定的。mRNA 和 miRNA 表达谱的变化反映了能量利用途径的差异，这与 p53 途径影响细胞对线粒体功能障碍的反应的观点一致，并且至少一些控制可能嵌入胚胎细胞中特定的 mRNA/miRNA 网络中。
